Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo

CD26 or dipeptidyl peptidase IV (DP IV) is expressed on various cell types, including T cells, Although T cells can receive activating signals via CD2 6, the physiological role of CD26/DP IV is largely unknown. We used the rev ersible DP IV inhibitor Lys[Z(NO2)]-pyrrolidide (I40) to dissect the role o f DP IV in experimental autoimmune encephalomyelitis (EAE) and to explore t he therapeutic potential of DP IV inhibition for autoimmunity. I40 administ ration in vivo decreased and delayed clinical and neuropathological signs o f adoptive transfer EAE, I40 blocked DP IV activity in vivo and increased t he secretion of the immunosuppressive cytokine TGF-beta1 in spinal cord tis sue and plasma during acute EAE, In vitro, while suppressing autoreactive T cell proliferation and TNF-alpha production, I40 consistently up-regulated TGF-beta1 secretion. A neutralizing anti-TGF-beta1 Ab blocked the inhibito ry effect of I40 on T cell proliferation to myelin Ag, DP IV inhibition in vivo was not generally immunosuppressive, neither eliminating encephalitoge nic T cells nor inhibiting T cell priming. These data suggest that DP IV in hibition represents a novel and specific therapeutic approach protecting fr om autoimmune disease by a mechanism that includes an active TGF-beta1-medi ated antiinflammatory effect at the site of pathology.